While it is unlikely that obesity in humans is a single disease, most obesities in experimental animals and man are accompanied by hyperinsulinemia, inactivity, and altered diurnal rhythms of glucocorticoids. For these studies, we will use four animal models: 1) genetically obese Zucker rats (fafa), 2) genetically obese and diabetic Wistar Kyoto "fatty" rats (WKY-fafa), 3) genetically lean rats that become obese when fed a high fat/high sucrose diet, and 4) exercised rats that rapidly regain weight when they become inactive. Experiments are designed to: 1. Study mechanism(s) underlying hyperinsulinemia and its role in development and maintenance of obesity. Evidence is accumulating that the autonomic nervous system plays a key role in establishment and maintenance of hyperinsulinemia. However, studies of pancreatic insulin secretion are somewhat limited because isolated islets or isolated pancreata are dennervated. Using an in situ central nervous system (CNS)-intact pancreatic perfusion system, for the the first time, we will be able to directly study the contribution of the autonomic nervous system to increased insulin secretion in obesity. Our hypothesis is that autonomic control of the pancreas directly contributes to increased insulin secretion in many forms of obesity. We propose that the vagus nerve "over" stimulates insulin secretion via efferent (to the pancreas) neurons which are "hyperactive" and offset the afferent (to the brain) neurons which are inhibitory to the pancreas via CNS reflexes. We also propose that "obesity- resistant" and "obesity-susceptible" rats will be distinguished, in part, by shifts in the balance between autonomic control of insulin secretion 2. We will study the interaction of insulin and corticosterone replacement in diabetic and adrenalectomized (ADX) obese and lean Zucker rats on food intake, adiposity, and protein turnover. We hypothesize that insulin will be less effective in the obese in sparing negative effects of corticosterone on protein turnover. 3. We propose that key to weight regain after exercise in changes in sympathetic tone to the pancreas and altered thermogenesis. High fat diets increase this regain. 4. We will study the underlying mechanism by which obese rats modify their fat intake. We propose that decreased fat intake in the ADX obese rat is a function of a series of events which decreases the "hedonic" response of an animal to fat and is mediated through the opioid system.